Substituted ethyl alkyl isothiocyanates



United States Patent SUBSTITUTED ETHYL ALKYL ISOTHIOCYANATES Hein L. Klopping, Wilmington, DeL, assignor to E. I. du Pont de Nemours and Company, Wilmington, DeL, a corporation of Delaware No Drawing. Application February 25, 1954 Serial No. 412,659

8 Claims. (Cl. 260-454) I This invention relates to substituted ethyl alkyl isothiocyanates containing a central sulfur atom. More particularly, the invention is directed to beta-halo substituted ethyl mercapto alkyl isothiocyanates, beta-hydroxy substituted ethyl mercapto alkyl isothiocyanates, beta-halo substituted ethyl sulfinyl alkyl isothiocyanates, beta-hydroxy substituted ethyl sulfinyl alkyl isothiocyanates, beta-halo substituted ethyl sulfonyl alkyl isothiocyanates, and beta-hydroxy substituted ethyl sulfonyl alkyl isothiocyanates.

The compounds of my invention can be represented by the formula:

where R R and R can be the same or diiferent and represent hydrogen or an alkyl radical containing from 1 to 3 carbon atoms, Y is a divalent sulfur-containing group of the class consisting of S, SO, and S X is halogen or hydroxy radical, and n is an integer of from 2 to 6.

In contrast to the bis-isothiocyanates of the prior art, the compounds of Formula 1 are readily soluble in such inexpensive solvents as ethylene chloride, methylene 2,824,887 Patented Feb. 25, 1958 shown below: This list, however, is not in any way limitative.

Isothiocyanic acid, 2-(Z-hydroxyethylmercapto)-ethyl ester lsothiocyanic acid, 2-(-2-chloroethylmercapto)-ethyl ester Isothiocyanic acid, 2-(Z-chloroethylsulfinyl)-ethyl ester Isothiocyanic acid, 2-(2-chloroethylsulfonyl)-ethyl ester Isothiocyanic acid, 2-(2-chloropropylsulfonyl)ethyl ester Isothiocyanic acid, 2-(2-chlorobuty1sulfonyl) ethyl ester ethyl ester Isothiocyanic acid, 2-(2-fiuoroethylsulfonyl)ethyl ester Isothiocyanic acid, 2-(2-iodethylsulfonyl)-ethyl ester Isothiocyanic acid, 3-(2-chloropropylmercapto)-n-propyl ester Isothiocyanic acid, 2-(2-chloro-2-methylpropylsulfinyl)- ethyl ester Isothiocyanic acid, 2-(2-bromo-l-methylbutylsulfinyl)- 3o ethyl ester Isothiocyanic acid, 6-(Z-hydroxyethylsulfonyl)hexyl ester Isothiocyanic acid, 4-(2-hydroxy-2-methylpropylsulfonyl)- butyl ester The compound of Formula 1 can be prepared from known organic compounds by any of a variety of methods.

chloride, chloroform, dichloroethane, acetone, methyl species falling within generic claim 1.

HCl-H1NCHr-CHa-Cl NaS-CHa-CHa-OH lNaOH HCl-HzN-CHr-CHFSOr-CHa-CHz-Cl (V11) ethyl ketone, benzene, and toluene.

The sulfides of The starting materials, beta-chloroethylaminehydro- Formula 1 are also soluble in aliphatic hydrocarbons such chloride and beta-mercaptoethanol, and two intermediate as, for example, n-heptane.

- Illustrative compounds of the present invention are compounds, identified above as I and H, are known.

beta-Chloroethylamine hydrochloride can be prepared Isothiocyanic acid, 2-(2-chloro-l-methylpentylsulfonyl)- where R R R i and n have the-same significance as m from ethanolamine.andconcentrated hydrochloric acid 1 at a temperature of 150460 C. [Ber. 38, 3130 (1905)] or from ethanolamine hydrochloride and SOC1 [1. Am. Chem. Soc. 63,3125 (1941 ,heta-Mercaptoethanol is 7 mostconveniently prepared from ethylene oxideandhw drogen sulfide.

. The compounds identified asIII, IV, V, VI, VIII-and X are products of the present invention. Of these compounds, 'l: prefer the sulfoxides (V and VI) over the sulfides (III and'IV) and the sulfones '(VIII andX) over r the sulfoxides. e

Broadly speaking, I prefer thejsulfones of Formula 1 over the sulfoxides and-sulfides of Formula 1. e The sulfides are the least preferred species. The ethyllesters are preferred. to the: higher, esters andthe halogenated more; The starting materials maybe represeutedas' follows:

HO-C-(J-SH it. I I. 7 and V s a. Cl-(CHzMNH HCl Formula 1.

Themercapto alcohols of Formulal'may be prepared by a variety of known methods. One method comprises i '35 Water may.also be employed as a solvent.

refluxing the chloro compound with NaSHfin alcohol. An alternative method com V prises the stepsshown'in. the following diagram:

, 4 and s. V H H V V R1(J=Ra V Olefins 'of Formula 5 yield mercapto alcohols 0f the for- 'mula V v r V z TRI- '3CB2SH V t V r i )H. while those of Formula -6 yield 'a mixture of .n'n l nrt R1 3--c'i- -R;: and nrt rh- -m his in H on 7 stirring is not impeded by the precipitating sodiumichlo These two components can:be separated by distillation.

The chloroalkylamine of Formula ,3 can also be prepared by one of several methods. For examplego-chloro-l-aminohexanehydrochloride can be prepared trout l,6-dichlorohexane and potassium ph'thalimide.

The initial condensation betweenthe'beta-mercapto alcohol of Formula 2. is preferably efiected in the pres,- ence of two equivalents of-a base, such as, .for example,

.alkanol to its metal salt. e The condensation is preferably carried out in a solvent 1 in which both reactants are soluble such as, for example,

% ethanol is a particularly preferred 7 a lower alkanol; solvent. The reaction proceeds well at thereflux temperature, of ethanol. -The ,by-product' of thereaction, sodium chloride, can be removed by simple filtration.

The qua ntity of solvent may vary within ratherwide limits. At least enoughfishouldbe present such that ride.

The second step in my general process of preparing the products of this invention involves the replacement of a hydroxy group by chlorine. Any of several methods may be employed to eifect this replacement; Compound higher than the reflux temperature of concentrated hydrochloric acid, say, at about-160" C.

to be prepared having R and R hydrogen and R alkyl, V

the synthesis steps are asv follows:

' The sulfur adds exclusively to the alpha carbon atom.

Compounds of Formulaizwherein R is alkyl and with the scheme:

Still other methods of preparing compounds'of For- 7 R and R are hydrogen can 'be prepared in accordance.

Alternatively, compound I, or generically speaking,

omega-hydroxyalkyl-omega-aminoalkyl sulfide, can be V refluxed with'thionyl chloride or phosphorus pentachlo ride in an organic, solvent such as, for instance, chloroform. In these alternative methods, protection of the analogs of H from. I, such agents as for example aqueous hydrobromic acid, aqueous hydroiodic acid, thionyl bromide, or phosphorus pentabromide can be employed. j V

The oxidation of a sulfide of the formula V V r V V R3 R1 S=CN- -(CH;)...S--+Ri where n, X, R R and R have the samef significance 7 as in'Formula 1, to the corresponding sulfoxide is pref-, erably 'eflEected inacetic acid using hydrogen peroxide.

'For optimum yield the reaction" mixture should be maintained at 25-35 C., although'satisfactory. yields are'ob' tained over a much wider range, say, from about '15 C to the reflux temperature of acetic acid." It is preferred practice to dilute 30% hydrogen peroxide with approximately an equal volume of acetic acid and add ture dropwise to a solution of the aforementioned Sulfide 1111 tic acid. The i rmatiqn of tar y lay-product can be assess? substantially eliminated by avoiding an excess of hydrogen peroxide. 7

The oxidation of sulfide sulfur in a compound having the formula to a sulfone can also be effected with hydrogen peroxide, preferably by adding the theoretical amount of hydrogen peroxide in aqueous solution to an aqueous solution of the sulfide at a temperature below 40 C. The sulfone can then be reacted with thiophosgene. Oxidation of a sulfide (II) to a sulfone (VII) can also be effected satisfactorily using dilute peracetic acid in aqueous medium at temperatures below 3.

The replacement of an amino group by an isothiocyano is effected by use of CSC1 and NaOH. This step corresponds on the schematic diagram to the conversion of I to IV, II to I11, IX to X and VII to VIII. When the compound identified as VII is subjected to CSCl and NaOH, a mixture of VIII and a vinyl derivative, which is described in my copending application Serial No. 412,660, now U. S. Patent No. 2,785,190 filed concurrently herewith, is obtained. If an excess of sodium hydroxide is used, complete dehydrohalogenation of the intermediate VIII takes place. I have found surprisingly that dehydrohalogenation can be completely prevented by replacing sodium hydroxide by sodium bicarbonate.

When compound II or an omega-chloroalkyl-omegaaminoalkyl sulfide hydrochloride is treated with thiophosgene and base, dehydrohalogenation does not take place.

As indicated above, the compounds of my invention are readily soluble in chlorinated hydrocarbons such as, for instance, chloroform, methylene chloride, dichloroethane, and the like. They are also very soluble in benzene, toluene, acetone and methyl ethyl ketone. They are, however, insoluble in water.

The compounds of the present invention are highly potent fungicides, insecticides and miticides. They are particularly useful in the control of fungus attack on seeds, plants, and vegetable crops and on other materials. They find further use as pre-harvest dehydrating or wilting agents. At concentrations higher than those which afford complete control of fungal diseases of plants and crops, my compounds exert an unexpected type of herbicidal activity. Leaves treated with the compounds dehydrate, collapse but remain green.

In order to better understand the nature of my invention, reference should be had to the following illustrative examples:

EXAMPLE 1 Preparation of isothiocyanic acid, 2- (Z-hydroxyethylmercapto)ethy1 ester To a solution of 368 g. of 85% potassium hydroxide in 2 liters of 95% ethyl alcohol, there is added 219 g. of beta-mercaptoethanol. The solution is stirred and refluxed as 327 g. of beta-chloroethylamine hydrochloride, dissolved in 700 ml. of 95% ethyl alcohol, are added over a period of one hour. The reaction mixture is stirred for a period of 5 hours. After the mixture is allowed to stand overnight, it is filtered. The potassium chloride on the filter is washed with alcohol, and the filtrate is combined with the washings. The alcohol is removed from the filtrate by evaporation in vacuo, and the oil residue is distilled under a high vacuum. The fraction boiling at l10-l20/0.9 mm. is collected and redistilled to give beta-aminoethyl-beta-hydroxyethyl sulfide. It is a colorless oil, B. P. 105-108/0.l5 mm., n =1.5282.

A solution of 12.1 grams of beta-hydroxyethyl-betasolution is vacuum concentrated to an oil.

aminoethyl sulfide in ml. of water is cooled in ice and stirred. Ten mls. of concentrated hydrochloric acid and a solution of g. of 'thiophosgene in ml. of chloroform are added to the cooled sulfide solution. Into the resulting mixture there is added dropwise a solution of 12 grams of sodium hydroxide in 60 ml. of water. The pH of the reaction mixture is kept below 7 during the dropwise addition of base. When the mixture no longer turns acidic, addition of base is stopped. The neutralized mixture is stirred for a period of about one hour.

The chloroform layer is separated, and combined with the chloroform washing of the aqueous layer. The combined chloroform extract is dried over anhydrous sodium sulfate, treated with Darco and filtered. The filtrate is evaporated to dryness. The residue is a yellow oil and consists essentially of 2-(2-hydroxyethyl-mercapto)ethyl isothiocyanate.

Analysis.Calcd. for C H ONS C36.78, H 5.55, N 8.58, S 39.28. Found: C 36.82, H 5.74, N 8.62, S 39.29.

EXAMPLE 2 Preparation of isothiocyanic acid, 2-(2-chl0r0ethylmercapto) ethyl ester A solution consisting of 181.7 g. of beta-hydroxyethylbeta-aminoethyl sulfide (prepared as in Example 1) in 1800 ml. of chloroform is stirred and heated to reflux. A solution of 357 g. of thionyl chloride in 220 ml. of chloroform is added dropwise. The reaction mixture is refluxed gently during the thionyl chloride addition. The addition takes three hours. After the mixture has stood overnight, the solid is collected on a filter, washed with chloroform, and dried. The resulting beta-chloroethylbeta-aminoethyl sulfide hydrochloride melts at 7779 C.

A solution of 17.6 g. of beta-chloroethyl-beta-aminoethyl sulfide hydrochloride in ml. of water is cooled in ice. A solution of 11.5 g. of thiophosgene in 170 ml. of chloroform is added all at once. While the mixture is stirred, a solution of 12 g. of sodium hydroxide in 60 ml. of water is added dropwise until the mixture no longer turns acidic on stopping the addition of base. Stirring is continued for one hour. Then the chloroform layer is separated, combined with chloroform washings of the aqueous layer, dried over anhydrous sodium sulfate, treated with Darco, filtered, collected and evapo rated to dryness in vacuo. The oily residue is distilled in vacuo. The light yellow liquid consisting essentially of isothiocyanic acid, 2-(2-chloroethylmercapto)ethyl ester boiling at l16118/1 mm. is collected.

Analysis.Calcd. for C H NS Cl: C 33.05, H 4.43, N 7.71. Found: C 33.21, H 4.57, N 7.74.

EXAMPLE 3 Preparation of isothiocyanic acid, 2-(2-ehlor0ethylsulfinyl) ethyl ester A solution of 15 g. of isothiocyanic acid, 2-(2-chloroethylmercapto) ethyl ester (prepared as in Example 2) in 75 ml. of glacial acetic acid is stirred. A solution of 11.5 g. of 29% hydrogen peroxide in 11.5 ml. of glacial acetic acid is added dropwise over a period of one hour. The temperature of the mixture is kept at 30. Stirring of the mixture is continued for five hours. Then the The oil crystallizes on prolonged cooling in ice. The crystals are purified by dissolving in chloroform at room temperature, adding carbon tetrachloride until the solution becomes cloudy, and cooling in ice. The purified crystals of the desired ester melt at 55-5 8 C.

Analysis.Calcd. for C H ONS Cl: C 30.37, H 4.08, N 7.08, S 32.43. Found: C 30.72, H 4.08, N 7.18, 8 32.47.

A solution of 58 g. beta-chloroethyl-beta-amino-ethyl sulfide hydrochloride (prepared as'in Example 2) in 600 V of water-11's stirred and cooled in an ethanol-ice mix-- ture. ;A sloutioncf 107ml] of 40% peraceticacid in 600 ml. of Water is' added dropw'ise. The temperature of the reaction rnjxture iskept below 3". The addition The mixture is stirred'for one at temperatures below 3, then the temperature of the.

takes 75 minutes.

mixture -is allowed to'rise slowly to room temperature while it is stirred "for four additionalhours. "After the mixture has stood overnight, it is vaccum concentrated to'a syrup. This syrup is cooled in ice and rubbed with acetone until crystallization iscomplete. The oily crystals melt at 130440". After recrystallization from 400 ml.

of a 1:1 mixture of absolute alcohol and 95% ethyl alco hol, the crystals of beta-chloroethyl-beta-aminoethyl' sulfone hydrochloride melt atl53-155 C.

Analysis.-Calcd. for C H G NSCI C 23.08, H 5.28, N 6.73; Found: C 23.26, H 5..33, N 6,7 2.

A solution of 34 g; of beta chloroethyl-beta amino-' ethylsulfone hydrochloride in 340 ml; of water is stirred and cooled in ice. in 340 ml. ofchloroforrn is added in a single batch. Then a solution of 41 g. of sodium bicarbonate in 440 mLof water is added dropwiseoveraperiod of three hours. The pH of thereaction mixture is kept below 7- at all times. 5 i

A solution of 14ml. of .thiophosgene The chloroform layer is separated, combined ,with r chloroform washings of the aqueous layer, .dried over anhydrous sodium sulfate,@ treated with Da'rco, filtered, collected, and vacuum concentrated to drynessi The residue; a pale yellow oil, crystallizes on standing. 'The crystals are ground with n-hexane, filtered ofi and' dried. The crystalline product, which is isothiocyanic acid, .2- (2-chlroroethylsulfonyl) ethyl ester, melts at 535 54 C.

Analysis.Calcd. for C' H O NS Cl: C 28.10, H 3.73,

where R R and R are members of the class consisting.

where R R5 and are members of the-class consisting V ofihydrogen and alkylradicals' hayingfrom l to 3 carbon atoms, X is a memberof thegroup consisting of halogen" and hydroxy radicals, and n iisan integer of'frqmfL-to 6.;

where R R2 and R are members of the class consisting of hydrogen and 'alkyl radicals having from .1 to 3 carbon atoms, X is a member of the group consisting of halogen" V and hydroxy radicals, and nis an integer of from 2 to6. 5. Isothiocyanic acid, 2-(l-hydroxyethylmercapto)- ethyl ester. r

N 6.55,' S 30.01, Cl 16.59. .Foundf 28.35 H 3.96,

N 6.62, S 30.38, Cl 1 6.63.

I claim:

l. A compound havingthe formula V 7 R2 Rs m-b-t'a-sr-wmn =o=s v of hydrogen and alkyl radicals having from lto 3 carbon atoms, X is a member of the group consisting of halogenand hydroxy radicals Y is a divalent radical of the class where R R5 and R are members ofithe class consisting ester. r a

7. lsothiocyanic' acid, 2-(Z-thlorbethylsulfiriyl)ethyl ester. 8. Is othi ocyanic acid, '2-'(2-chloroethylsulfonyl) ethyl ester. I V

'Referelices-Citedinthe this patent UNITED STATES ,PATENTS p,

2,139,335 j Shoemaker. Dec. 6, 7 2,372,809: -Bruson Apr. 3, 1945 2,394,915 7 Jones 2.; T Feb. 12, 1946 r "FOREIGN PATENTS 2 f 822,339 j Germany f -'Ncv. 26,1951

OTHER? REFERENCE 7 p s'one or Synthesis; CQll; vol. 1 941), page 165.

6. Isothiocyanic acid, 2-(2-chloroethylmercapto)-ethyl U. S. DEPARTMENT OF COMMERCE PATENT OFFICE CERTIFICATE OF CORRECTION Patent Nos 2,82% 88? Hein Lo Klopping It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 1, line 27, before the formula insert the lumber "lo";

i '4? a i n column 2, line 23, for "2=-(2=1odethylsulfonyl) read m d ge=1odoeuhyleui= fongl= column '7, line 14, for "vaccum" read me vacuum n Signed and sealed this 20th day of May 1958.,

At'iaest:

L i a W H MINE ROBERT C. WAT$ON Comnissioner of Patents Attesting Officer 

1. A COMPOUND HAVING THE FORMULA 